This is a renewal application for a K24 (Mid-Career Investigator Award) for Katherine Luzuriaga, M.D., a physician-scientist with clinical training in pediatric infectious diseases and research training in viral immunology. Her research has examined the viral and immunopathogenesis of pediatric HIV-1 infection, with the goal of improving prevention and treatment strategies. Dr. Luzuriaga's work over the past funding period has resulted in 11 publications in high quality journals, renewal of an RO1 focused on characterizing HIV-specific CD8+ T cells (AI32391), and new RO1 funding (HD40450) for work examining cytomegalovirus specific CD8+ T cells in infants. As a faculty member at the University of Massachusetts Medical School (UMMS), Dr. Luzuriaga enjoys and is highly committed to training the next generation of scientists. Over the past 4 years of support, she has mentored 2 graduate students who have gone on to post-doctoral fellowships and careers in patient-oriented research. In addition, she has mentored and continues to mentor 3 post-doctoral fellows (2 M.D./Ph.D.) and a junior faculty member. In this renewal application, a mentoring plan is outlined that will continue to provide trainees with a range of activities that will prepare them as independent investigators in patient-oriented research. Renewal of her Mid-Career Award will permit the candidate to continue to devote the majority of her time to patient-oriented research and mentoring the next generation of scientists. Work outlined in the renewal application will continue our studies characterizing the generation, specificity, and function of HIV-1 specific CD4+ and CD8+ T cell responses in young infants and their relationship to HIV-1 replication. Collectively, these projects address the hypotheses that the role of HIV-1 specific CD8+ T cells in the pathogenesis of vertical HIV-1 infection is dependent not only on the timing of detection, magnitude, and breadth of CD8+ T cell responses but also on the founder viral sequence, the availability of CD4+ T cell help, and on CD8+ T cell specificity and functional properties. The following specific aims will be examined: 1) To sequentially examine the timing of detection, magnitude, specificity, and functional properties of HIV-1-specific CD8+ T lymphocyte responses in young, HIV-1 infected infants; 2) To evaluate maternal and early infant sequences for CD8+ T cell escape variants and for evidence of CD8+ T cell selective pressure in vivo; 3) To conduct Phase I clinical trials that examine the safety and immunogenicity of multivalent pox-based vaccines in children with long-term control of viral replication following early, ^potent combination ART. Data from these studies will improve our understanding of the pathogenesis of early pediatric HIV infection and contribute to the development of strategies to prevent or modify pediatric HIV-1 infection.